TY - JOUR
T1 - A hereditary spastic paraplegia predominant phenotype caused by variants in the NEFL gene
AU - Mul, Karlien
AU - Schouten, Meyke I
AU - van der Looij, Erica
AU - Dooijes, Dennis
AU - Hennekam, Frederic A M
AU - Notermans, Nicolette C
AU - Praamstra, Peter
AU - van Gaalen, Judith
AU - Kamsteeg, Erik-Jan
AU - Verbeek, Nienke E
AU - van de Warrenburg, Bart P C
N1 - Funding Information:
BvdW receives research support from the Radboud university medical center , uniQure , Gossweiler Foundation , Hersenstichting , and ZonMW . The other authors report no disclosures.
Publisher Copyright:
© 2020 The Authors
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/11
Y1 - 2020/11
N2 - INTRODUCTION: This study reports a large series of patients with a clinical picture dominated by spastic paraplegia in whom variants in the NEFL gene, a known cause for Charcot-Marie-Tooth disease, were identified.METHODS: Index patients referred for a suspicion of hereditary spastic paraplegia (HSP) were clinically assessed and genetic analysis by next-generation sequencing was undertaken. Additional family members were clinically examined and subjected to targeted testing.RESULTS: We identified two different heterozygous dominant variants in the NEFL gene in 25 patients from 14 families. Most of them (21/25) had a clinical diagnosis of HSP, often with a concomitant clinical diagnosis of polyneuropathy (16/21). Two patients were identified with a polyneuropathy with a pyramidal reflex pattern, but without spasticity. Two patients had isolated polyneuropathy. Out of the 21 patients with a diagnosis of HSP, two had co-occurring cerebellar signs. The c.262A > C p.(Thr88Pro) variant was detected in 13 families. Genealogical analysis showed shared ancestors or a similar geographical origin in 12, suggesting a founder effect. The other variant, c.296A > C p.(Asp99Ala), was found in only one family, in which limited segregation analysis could be performed.DISCUSSION: Variants in the NEFL gene can cause HSP, with or without co-existing polyneuropathy, and should be included in diagnostic testing strategies for HSP patients.
AB - INTRODUCTION: This study reports a large series of patients with a clinical picture dominated by spastic paraplegia in whom variants in the NEFL gene, a known cause for Charcot-Marie-Tooth disease, were identified.METHODS: Index patients referred for a suspicion of hereditary spastic paraplegia (HSP) were clinically assessed and genetic analysis by next-generation sequencing was undertaken. Additional family members were clinically examined and subjected to targeted testing.RESULTS: We identified two different heterozygous dominant variants in the NEFL gene in 25 patients from 14 families. Most of them (21/25) had a clinical diagnosis of HSP, often with a concomitant clinical diagnosis of polyneuropathy (16/21). Two patients were identified with a polyneuropathy with a pyramidal reflex pattern, but without spasticity. Two patients had isolated polyneuropathy. Out of the 21 patients with a diagnosis of HSP, two had co-occurring cerebellar signs. The c.262A > C p.(Thr88Pro) variant was detected in 13 families. Genealogical analysis showed shared ancestors or a similar geographical origin in 12, suggesting a founder effect. The other variant, c.296A > C p.(Asp99Ala), was found in only one family, in which limited segregation analysis could be performed.DISCUSSION: Variants in the NEFL gene can cause HSP, with or without co-existing polyneuropathy, and should be included in diagnostic testing strategies for HSP patients.
KW - Genotype-phenotype
KW - Hereditary spastic paraplegia
KW - NEFL gene
KW - Polyneuropathy
UR - http://www.scopus.com/inward/record.url?scp=85091392665&partnerID=8YFLogxK
U2 - 10.1016/j.parkreldis.2020.09.016
DO - 10.1016/j.parkreldis.2020.09.016
M3 - Article
C2 - 32979786
SN - 1353-8020
VL - 80
SP - 98
EP - 101
JO - Parkinsonism & Related Disorders
JF - Parkinsonism & Related Disorders
ER -